Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). METHODS: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. RESULTS: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. CONCLUSIONS: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. LAY SUMMARY: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.

Prognostic value of multiparametric magnetic resonance imaging, transient elastography and blood-based fibrosis markers in patients with chronic liver disease.

BACKGROUND & AIMS: Liver cT1 , liver T1 , transient elastography (TE) and blood-based biomarkers have independently been shown to predict clinical outcomes but have not been directly compared in a single cohort of patients. Our aim was to compare these tests' prognostic value in a cohort of patients with compensated chronic liver disease. METHODS: Patients with unselected compensated liver disease aetiologies had baseline assessments and were followed up for development of clinical outcomes, blinded to the imaging results. The prognostic value of non-invasive liver tests at prespecified thresholds was assessed for a combined clinical endpoint comprising ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation and mortality. RESULTS: One hundred and ninety-seven patients (61% male) with median age of 54 years were followed up for 693 patient-years (median (IQR) 43 (26-58) months). The main diagnoses were NAFLD (41%), viral hepatitis (VH, 25%) and alcohol-related liver disease (ArLD; 14%). During follow-up 14 new clinical events, and 11 deaths occurred. Clinical outcomes were predicted by liver cT1  > 825ms with HR 9.9 (95% CI: 1.29-76.4, P = .007), TE > 8kPa with HR 7.8 (95% CI: 0.97-62.3, P = .02) and FIB-4 > 1.45 with HR 4.09 (95% CI: 0.90-18.4, P = .05). In analysis taking into account technical failure and unreliability, liver cT1  > 825 ms could predict clinical outcomes (P = .03), but TE > 8kPa could not (P = .4). CONCLUSIONS: We provide further evidence that liver cT1 , TE and serum-based biomarkers can predict clinical outcomes, but when taking into account technical failure/unreliability, TE cut-offs perform worse than those of cT1 and blood biomarkers.

Comparison of liver T1 relaxation times without and with iron correction in pediatric autoimmune liver disease.

BACKGROUND: Magnetic resonance imaging (MRI) T1 relaxometry (mapping) has been reported as a quantitative biomarker of liver injury due to inflammation and fibrosis. OBJECTIVE: To assess the relationship between liver MRI T1 relaxometry measurements obtained using a modified Look-Locker inversion recovery (MOLLI) pulse sequence without and with iron (T2*) correction (cT1) in pediatric autoimmune liver disease. MATERIALS AND METHODS: This cross-sectional study was institutional review board-approved, with informed consent obtained. MRI was acquired at 1.5 T in patients participating in an autoimmune liver disease registry. T1 relaxometry was performed using a MOLLI sequence with a 5(3)3-s acquisition strategy. A multi-echo gradient echo sequence was used to measure liver T2*. Non-iron-corrected native T1 (ms), calculated as the mean of four slices through the mid-liver, was measured using T1 parametric maps generated off-line. A proprietary T2* correction (Perspectum Diagnostics, Oxford, UK), blinded to native T1 values, calculated cT1 values. The relationship between native T1 and cT1 measurements was assessed using Spearman rank correlation and Bland-Altman analyses. RESULTS: Forty-eight patients with a mean (standard deviation [SD]) age of 15.2 (4.1) years were included. Mean (SD) liver native T1 was 651.2 (123.9) ms and mean (SD) cT1 was 919.5 (86.8) ms, with excellent positive correlation between values (r=0.91 [95% confidence interval (CI): 0.85-0.95]; P<0.0001). Mean bias between native T1 and cT1 measurements was 268.3 ms (95% limits of agreement: 131.9-404.7 ms). CONCLUSION: There is excellent positive correlation between liver native T1 and cT1 measurements in pediatric patients with autoimmune liver disease. This relationship brings into question the need to perform T1 iron correction in this patient population. T1 and cT1 measurements are not interchangeable, however, due to considerable systematic bias with cT1 values being considerably higher.

Multiparametric magnetic resonance imaging predicts clinical outcomes in patients with chronic liver disease.

BACKGROUND & AIMS: Multiparametric magnetic resonance (MR) imaging has been demonstrated to quantify hepatic fibrosis, iron, and steatosis. The aim of this study was to determine if MR can be used to predict negative clinical outcomes in liver disease patients. METHODS: Patients with chronic liver disease (n=112) were recruited for MR imaging and data on the development of liver related clinical events were collected by medical records review. The median follow-up was 27months. MR data were analysed blinded for the Liver Inflammation and Fibrosis score (LIF; <1, 1-1.99, 2-2.99, and ⩾3 representing normal, mild, moderate, and severe liver disease, respectively), T2∗ for liver iron content and proportion of liver fat. Baseline liver biopsy was performed in 102 patients. RESULTS: Liver disease aetiologies included non-alcoholic fatty liver disease (35%) and chronic viral hepatitis (30%). Histologically, fibrosis was mild in 54 (48%), moderate in 17 (15%), and severe in 31 (28%) patients. Overall mortality was 5%. Ten patients (11%) developed at least one liver related clinical event. The negative predictive value of LIF<2 was 100%. Two patients with LIF 2-2.99 and eight with LIF⩾3 had a clinical event. Patients with LIF⩾3 had a higher cumulative risk for developing clinical events, compared to those with LIF<1 (p=0.02) and LIF 1-1.99 (p=0.03). Cox regression analysis including all 3 variables (fat, iron, LIF) resulted in an enhanced LIF predictive value. CONCLUSIONS: Non-invasive standardised multiparametric MR technology may be used to predict clinical outcomes in patients with chronic liver disease.

Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease.

BACKGROUND & AIMS: With the increasing prevalence of liver disease worldwide, there is an urgent clinical need for reliable methods to diagnose and stage liver pathology. Liver biopsy, the current gold standard, is invasive and limited by sampling and observer dependent variability. In this study, we aimed to assess the diagnostic accuracy of a novel magnetic resonance protocol for liver tissue characterisation. METHODS: We conducted a prospective study comparing our magnetic resonance technique against liver biopsy. The individual components of the scanning protocol were T1 mapping, proton spectroscopy and T2* mapping, which quantified liver fibrosis, steatosis and haemosiderosis, respectively. Unselected adult patients referred for liver biopsy as part of their routine care were recruited. Scans performed prior to liver biopsy were analysed by physicians blinded to the histology results. The associations between magnetic resonance and histology variables were assessed. Receiver-operating characteristic analyses were also carried out. RESULTS: Paired magnetic resonance and biopsy data were obtained in 79 patients. Magnetic resonance measures correlated strongly with histology (r(s)=0.68 p<0.0001 for fibrosis; r(s)=0.89 p<0.001 for steatosis; r(s)=-0.69 p<0.0001 for haemosiderosis). The area under the receiver operating characteristic curve was 0.94, 0.93, and 0.94 for the diagnosis of any degree of fibrosis, steatosis and haemosiderosis respectively. CONCLUSION: The novel scanning method described here provides high diagnostic accuracy for the assessment of liver fibrosis, steatosis and haemosiderosis and could potentially replace liver biopsy for many indications. This is the first demonstration of a non-invasive test to differentiate early stages of fibrosis from normal liver.

The effectiveness of magnetic resonance imaging (MRI) iron corrected T1 in monitoring metabolic dysfunction-associated steatohepatitis in obesity following bariatric surgery and lifestyle modification: a prospective cohort study.

Background: Bariatric surgery and lifestyle modification are important treatments for obesity, a risk factor for metabolic dysfunction-associated steatohepatitis (MASH). Studies have related weight reduction with changes in MASH, however, few have used imaging to investigate effects on liver health. We evaluated differences in liver response to obesity treatment using disease activity iron corrected T1 (cT1) and proton density fat fraction (PDFF) in patients with both obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: Thirty-four patients with obesity and MASLD were recruited between March 2019 to February 2022 from a tertiary hospital in this longitudinal study; 13 underwent laparoscopic sleeve gastrectomy (LSG) alongside intraoperative liver biopsy, and 21 underwent a 4-month lifestyle modification program (LMP). All patients had multi-parametric magnetic resonance imaging (MRI) at baseline and 4-months. Diagnostic accuracy to identify MASH was assessed using the area under receiver operating characteristic (AUROC) curve. Results: Four (31%) of patients in the LSG group had MASH [non-alcoholic steatohepatitis (NAS) activity score ≥4] on liver biopsy. PDFF and cT1 correlated with the NAS activity score [r=0.81, 95% confidence interval (CI): 0.453 to 0.943, P<0.001] and (r=0.70, 95% CI: 0.228 to 0.907, P=0.008, respectively). There was good AUROC curve for cT1 (0.89, 95% CI: 0.67 to 1.00, P=0.031) and PDFF (0.83, 95% CI: 0.57 to 1.00, P=0.064) to identify MASH. At follow-up, weight reduction -22.8% (P=0.013) vs. -1.3% (P=0.262) resulted in cT1 reduction of -8.04% (864 ms, P=0.025) vs. -3.87% (907 ms, P=0.083) in the LSG vs. LMP group, respectively. Significant differences between interventions were observed for percentage PDFF decrease (-64.52% vs. -29.16%, P=0.001). Both biomarkers were significantly reduced in the LSG group (cT1 by -8.04%, P=0.025, PDFF by -64.52%, P=0.012), while only PDFF (-29.16%, P=0.012) was significantly reduced in the LMP group. Conclusions: MRI biomarkers may have some utility to monitor MASH following intervention in patients with obesity allowing objective comparison between intervention strategies. Compared to LMP, LSG was more effective in improving liver health.

Physical activity is inversely associated with hepatic fibro-inflammation: A population-based cohort study using UK Biobank data.

Background & Aims: Physical activity (PA) is recommended in the management of non-alcoholic fatty liver disease (NAFLD) given its beneficial effects on liver fat and cardiometabolic risk. Using data from the UK Biobank population-cohort, this study examined associations between habitual PA and hepatic fibro-inflammation. Methods: A total of 840 men and women aged 55-70 years were included in this cross-sectional study. Hepatic fibro-inflammation (iron-corrected T1 [cT1]) and liver fat were measured using MRI, whilst body fat was measured using dual-energy X-ray absorptiometry. PA was measured using accelerometry. Generalised linear models examined associations between PA (light [LPA], moderate [MPA], vigorous [VPA], moderate-to-vigorous [MVPA] and mean acceleration) and hepatic cT1. Models were fitted for the whole sample and separately for upper and lower median groups for body and liver fat. Models were adjusted for sociodemographic and lifestyle variables. Results: In the full sample, LPA (-0.08 ms [-0.12 to -0.03]), MPA, (-0.13 ms [-0.21 to -0.05]), VPA (-1.16 ms [-1.81 to -0.51]), MVPA (-0.14 ms [-0.21 to -0.06]) and mean acceleration (-0.67 ms [-1.05 to-0.28]) were inversely associated with hepatic cT1. With the sample split by median liver or body fat, only VPA was inversely associated with hepatic cT1 in the upper median groups for body (-2.68 ms [-4.24 to -1.13]) and liver fat (-2.33 [-3.73 to -0.93]). PA was unrelated to hepatic cT1 in the lower median groups. Conclusions: Within a population-based cohort, device-measured PA is inversely associated with hepatic fibro-inflammation. This relationship is strongest with VPA and is greater in people with higher levels of body and liver fat. Lay summary: This study has shown that people who regularly perform greater amounts of physical activity have a reduced level of inflammation and fibrosis in their liver. This beneficial relationship is particularly strong when more intense physical activity is undertaken (i.e., vigorous-intensity), and is most visible in individuals with higher levels of liver fat and body fat.

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Associations between MRI T1 mapping, liver stiffness, quantitative MRCP, and laboratory biomarkers in children and young adults with autoimmune liver disease.

PURPOSE: Define relationships between quantitative magnetic resonance imaging (MRI) metrics and clinical/laboratory data in a pediatric and young adult cohort with autoimmune liver disease (AILD). MATERIALS AND METHODS: This prospective, cross-sectional study was institutional review board-approved. Patients enrolled in an institutional AILD registry were divided into groups: (1) autoimmune hepatitis (AIH) or (2) primary sclerosing cholangitis (PSC)/autoimmune sclerosing cholangitis (ASC). Participants underwent serum liver biochemistry testing and research MRI examinations, including 3D magnetic resonance cholangiopancreatography (MRCP), magnetic resonance elastography (MRE), and iron-corrected T1 mapping (cT1). MRCP + and LiverMultiScan (Perspectum Ltd., Oxford, UK) were used to post-process 3D MRCP and cT1 data. Multiple linear regression models were used to assess relationships. RESULTS: 58 patients, 35 male, median age 16 years were included; 30 in the AIH group, 28 in the PSC/ASC group. After statistical adjustments for patient age, sex, presence of inflammatory bowel disease (IBD), specific diagnosis (PSC/ASC vs. AIH), and time from diagnosis to MRI examination, left hepatic bile duct maximum diameter was a statistically significant predictor of whole liver mean cT1, cT1 interquartile range (IQR), and MRE liver stiffness (p = 0.01-0.04). Seven laboratory values were significant predictors of whole liver cT1 IQR (p < 0.0001-0.04). Eight laboratory values and right hepatic bile duct median and maximum diameter were significant predictors of liver stiffness (p < 0.0001-0.03). CONCLUSIONS: Bile duct diameters and multiple laboratory biomarkers of liver disease are independent predictors of liver stiffness and cT1 IQR in pediatric patients with AILD.

Liver cT1 decreases following direct-acting antiviral therapy in patients with chronic hepatitis C virus.

PURPOSE: Direct-acting antiviral therapies (DAAs) for treatment of chronic hepatitis C virus (HCV) have excellent rates of viral eradication, but their effect on regression of liver fibrosis is unclear. The primary aim was to use magnetic resonance imaging (MRI) and spectroscopy (MRS) to evaluate changes in liver fibrosis, liver fat and liver iron content (LIC) in patients with chronic HCV following treatment with DAAs. METHODS: In this prospective study, 15 patients with chronic HCV due to start treatment with DAAs and with transient elastography (TE) > 8 kPa were recruited consecutively. Patients underwent MRI and MRS at baseline (before treatment), and at 24 weeks and 48 weeks after the end of treatment (EoT) for the measurement of liver cT1 (fibroinflammation), liver fat and T2* (LIC). RESULTS: All patients achieved a sustained virological response. Liver cT1 showed significant decreases from baseline to 24 weeks post EoT (876 vs 806 ms, p = 0.002, n = 15), baseline to 48 weeks post EoT (876 vs 788 ms, p = 0.0002, n = 13) and 24 weeks post EoT to 48 weeks post EoT (806 vs 788 ms, p = 0.016, n = 13). Between baseline and 48 weeks EoT significant reduction in liver fat (5.17% vs 2.65%, p = 0.027) and an increase in reported LIC (0.913 vs 0.950 mg/g, p = 0.021) was observed. CONCLUSION: Liver cT1 decreases in patients with chronic HCV undergoing successful DAA treatment. The relatively fast reduction in cT1 suggests a reduction in inflammation rather than regression of fibrosis.

Relationship between magnetic resonance imaging spleen T1 relaxation and other radiologic and clinical biomarkers of liver fibrosis in children and young adults with autoimmune liver disease.

BACKGROUND: Little is known about the relationships between MRI splenic T1 relaxation measurements and other radiologic and clinical markers of chronic liver disease, including the presence of radiologic portal hypertension. OBJECTIVE: To evaluate the relationships between MRI splenic T1 relaxation and other radiologic and clinical biomarkers of liver fibrosis, including the presence of radiologic portal hypertension, in children and young adults with autoimmune liver diseases (AILD). MATERIALS AND METHODS: Research MRI examinations performed at 1.5 T from 63 AILD registry participants were identified. Spleen T1 and iron-corrected T1 (cT1) relaxation measurements, liver cT1, liver/spleen stiffness, splenic length percentile for age, and presence of radiologic portal hypertension were recorded, along with demographic and laboratory data. The Mann-Whitney U test was used to compare continuous data between groups; Spearman correlation was used to evaluate associations. Areas-under-the-receiver operating characteristic curve (AuROC) was used to assess diagnostic performance. RESULTS: Mean age was 15.2 ± 4.1 years. Mean splenic T1 and cT1 values for the study population were 1158.0 ± 70.9 ms and 1436.0 ± 68.9 ms, respectively. Splenic T1 and cT1 values positively correlated with APRI and FIBROSIS-4 scores, splenic length percentile, liver cT1 values, and liver and spleen stiffnesses (p-values < 0.05). There was no significant relationship between splenic T1/cT1 and age (p-values > 0.05). Splenic T1 and cT1 values were higher in participants with vs. without radiologic portal hypertension (n = 18) (1213.4 ± 69.6 vs. 1135.4 ± 58.5 ms; p = 0.0001, and 1488.2 ± 64.8 vs. 1415.1 ± 59.1 ms; p = 0.0002). Splenic T1 and cT1 both demonstrated an AuROC of 0.81 for discriminating patients without and with portal hypertension (p-values < 0.0001). CONCLUSION: Splenic T1 relaxation is associated with other radiologic and clinical biomarkers of liver fibrosis, including radiologic portal hypertension, in children and young adults with AILD.

Multiparametric MRI for early detection of diffuse liver disease: an interview with David Breen.

David J Breen is Associate Professor of Radiology and previous Clinical Director of Radiology at University Hospital Southampton. His interests are in abdominal imaging and intervention, particularly of hepato-pancreato-biliary (HPB)and renal disease. He has a major interest in image-guided tumor ablation and improving outcomes from these procedures. He has previously served as Vice Chair of the NHS England Clinical Reference Group in Interventional Radiology and for the NIHR/NCRN Upper GI Clinical Studies Group.